The overall goal of this proposal is to define the mechanisms by which expression of CD44 isoforms containing the alternatively spliced exon v10 impact on the response of malignant hematopoietic cells to ionizing radiation and other therapies that mediate their effects via the induction of apoptosis. The PI hypothesizes that signals transduced via the homotypic interaction of alternatively spliced CD44 isoforms can both promote the development of malignant disease and protect tumor cells from therapeutic agents by modulating the cellular response to pro-apoptotic stimuli. Site-directed mutagenesis will be used to identify the precise sequence motifs present in exon v10 that promote adhesion between alternatively spliced CED44 isoforms and the role that such interactions may play in regulating the apoptotic response induced by ionizing radiation. Particular emphasis will be placed on characterizing the signal transduction events triggered by ligation of CD44 that modulate radiation sensitivity. In addition, efforts will be made to determine the possible involvement in both the regulation of CD44-mediated adhesion and the delivery of anti-apoptotic signals, of CD44RC, a novel alternatively spliced soluble CD44 isoform cloned in the PI's laboratory, which is differentially expressed by certain malignant hematopoietic cells. The first specific aim will be to define the molecular mechanisms by which the presence of exon v10 promotes CED44 mediated cell-cell adhesion. The second specific aim will characterize the downstream signal transduction events that are triggered by ligation of CD44, which alter cell survival following exposure to ionizing radiation and other pro-apoptotic stimuli. The third specific aim will be to determine the impact on cell survival following ionizing radiation of CD44RC, a novel soluble CD44 isoform cloned in the PI's laboratory. This isoform can bind to and activate the adhesive function of cell surface CD44.